Protecting podocytes: how good do we need to be?

Progression of many glomerular diseases has been firmly tied to a loss of podocytes, followed by a deterioration of glomerular architectural stability eventuating in segmental, and ultimately global, sclerosis. Recent studies have begun to clarify the nature of the autonomous (disease-independent) aspects of this process, as well as to explore mechanistically the ‘unreasonable effectiveness’ of angiotensin blockade in slowing glomerular disease progression. Quantitative monitoring of podocyte loss (e.g., to assess therapy) remains a challenge

A Proposal to Expand the Religious Services Exemption Under the Copyright Act

This article focuses on the religious services exemption to the Copyright Act. The religious services exemption is one of many exemptions that permit certain types of use without first obtaining permission from the copyright owner, or proving fair use. This article argues that the religious services exemption should be expanded to cover any work used in the course of services as well as the recording, broadcast, and transmission of the services. The first part of this article analyzes the existing religious services exemption under the Copyright Act to define the bounds that uses fall under the exemption. The article then proceeds to present a proposal for expanding the exemption to accommodate the needs of modern religious organizations. Next, the article addresses the Establishment Clause and the constitutionality of the current religious services exemption. Thereafter, the article demonstrates that the religious services exemption can defeat an Establishment Clause challenge by expanding the exemption to cover non-religious ventures, such as teaching in general. Finally, the article examines traditional fair use under copyright law, specifically how the fair use analysis will apply to works used during the course of religious services. The article concludes that the current religious services exemption is inadequate to meet the needs of a society of instant communication, which has changed the way religious organizations need to effectively communicate their religious messages. However, the proposed expansion would satisfy those needs as well as pass constitutional muster

I\u27ll Make Him an Offer He Can\u27t Refuse: A Proposed Model for Alternative Dispute Resolution in Intellectual Property Disputes

This article will discuss alternative dispute resolution in intellectual property disputes. A conceptual approach will be applied in an effort to better formulate the parties’ strategies towards litigation or alternative dispute resolution. Alternative dispute resolution (ADR) is a maturing area of the law, and its application to intellectual property disputes is complicated.1 These complications make any analysis difficult to organize. This article will discuss the underlying components of ADR and intellectual property disputes in a step-by-step fashion. Part I of this article discusses intellectual property rights and presents two conceptual interests underlying these rights. Deciding whether to litigate or pursue ADR demands a thorough understanding of what legal rights are in dispute. Part II focuses on the remedies available to intellectual property owners (potential liability to infringers) to effectively ascertain the “prize” of the dispute. Part III provides background information on various forms of ADR as well as the Alternative Dispute Resolution Act. This section will serve as guidance for later sections, primarily the proposal in Part V. Part IV analyzes the advantages/risks calculi for intellectual property owners and infringers in proceeding to trial or pursuing ADR. Part V presents a sophisticated proposal for dispute resolution in intellectual property disputes. Part VI discusses the effects of this proposal. The conceptual approach focusing on the parties’ underlying interests offers a pragmatic solution to the litigation/ADR dilemma. In this article, one crucial issue concerning intellectual property disputes emerges: the parties’ interests often align. With this realization, a system of ADR better serves the parties’ interests and creates tailored solutions to their complicated disputes

The Effect of a Gluten-Free Diet in Children With Difficult-to-Manage Nephrotic Syndrome

Case reports have linked childhood nephrotic syndrome to food sensitivity, including gluten. We report our experience with 8 children (6 boys, 2 girls; age at implementation of special diet 2–14 years) with difficult-to-manage nephrotic syndrome who were placed on a gluten-free diet for 3.4 ± 4.3 years (range, 0.6–14 years) and who had clinical improvement enabling reduction or discontinuation in steroid dosage

Podocytopenia and disease severity in IgA nephropathy

Podocytopenia and disease severity in IgA nephropathy.BackgroundIgA nephropathy is a common form of progressive glomerular disease, associated with proliferation of mesangial cells and mesangial deposition of IgA. The present study was designed to investigate functional and morphological covariates of disease severity in patients with IgA nephropathy.MethodsGlomerular hemodynamics, permselectivity and ultrastructure were studied in 17 adult patients with IgA nephropathy using inulin, para-aminohippuric acid (PAH) and 3H-Ficoll clearances and morphometric methods. A mathematical model of macromolecule permeation through a heteroporous membrane was used to characterize glomerular permselectivity. Controls consisted of 14 healthy living kidney donors and 12 healthy volunteers.ResultsThe patients were heterogeneous in their disease severity, but as a group had a decreased glomerular filtration rate (GFR) and increased urinary protein excretion compared to controls [63 ± 29 SD vs. 104 ± 23 mL/min/1.73 m2, P < 0.001, and (median) 1.34 vs. 0.11 g/day, P < 0.0001, respectively). A multivariate analysis of structural and functional relationships revealed GFR depression to be most strongly correlated with the prevalence of global glomerular sclerosis (t = -4.073, P = 0.002). Those patients with the most severe glomerular dysfunction had a reduced number of glomerular visceral epithelial cells (podocytes) per glomerulus. The degree of podocytopenia was related to the extent of glomerular sclerosis and of impairment of permselectivity and GFR, with worsening injury below an apparent threshold podocyte number of about 250 cells per glomerulus. There were no corresponding correlations between these indices of injury and the number of mesangial and endothelial cells.ConclusionsOur findings show that podocyte loss is a concomitant of increasing disease severity in IgA nephropathy. This suggests that podocyte loss may either cause or contribute to the progressive proteinuria, glomerular sclerosis and filtration failure seen in this disorder

Statistical methods for building better biomarkers of chronic kidney disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149268/1/sim8091.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149268/2/sim8091_am.pd

C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy

: The deposition of anti-podocyte auto-antibodies in the glomerular subepithelial space induces primary membranous nephropathy (MN), the leading cause of nephrotic syndrome worldwide. Taking advantage of the glomerulus-on-a-chip system, we modeled human primary MN induced by anti-PLA2R antibodies. Here we show that exposure of primary human podocytes expressing PLA2R to MN serum results in IgG deposition and complement activation on their surface, leading to loss of the chip permselectivity to albumin. C3a receptor (C3aR) antagonists as well as C3AR gene silencing in podocytes reduced oxidative stress induced by MN serum and prevented albumin leakage. In contrast, inhibition of the formation of the membrane-attack-complex (MAC), previously thought to play a major role in MN pathogenesis, did not affect permselectivity to albumin. In addition, treatment with a C3aR antagonist effectively prevented proteinuria in a mouse model of MN, substantiating the chip findings. In conclusion, using a combination of pathophysiologically relevant in vitro and in vivo models, we established that C3a/C3aR signaling plays a critical role in complement-mediated MN pathogenesis, indicating an alternative therapeutic target for MN

Plasma Zonulin Levels in Childhood Nephrotic Syndrome

Objective: We conducted this study to test the hypothesis that plasma zonulin levels are elevated in pediatric patients with nephrotic syndrome compared to healthy controls.Study Design: Plasma zonulin levels were measured by ELISA in 114 children enrolled in the NEPTUNE study. Clinical and laboratory data were retrieved from the NEPTUNE database.Results: The median age of the patients was 10 (IQR = 5 to 14) years, 59 were male, 64 had minimal change disease, 47 focal segmental glomerulosclerosis, median eGFR was 96 (IQR = 80 to 114) ml/min/1.73 m2, and median urine protein:creatinine ratio was 0.5 (IQR = 0.1 to 3.4) (g:g). The plasma zonulin level was 14.2 ± 5.0 vs. 10.2 ± 2.5 ng/ml in healthy adults in a report using the same assay kit, P = 0.0025. These findings were confirmed in an independent cohort of children with nephrotic syndrome compared to healthy age-matched controls, P = 0.01. Zonulin concentrations did not differ in children with minimal change disease vs. focal segmental glomerulosclerosis, frequently relapsing vs. steroid-dependent vs. steroid-resistant clinical course, and were not influenced by the immunosuppressive treatment regimen. There was no relationship between plasma zonulin levels and the absolute or percentage change in proteinuria from enrollment until the time of the zonulin assay.Conclusion: Plasma zonulin levels are elevated in childhood nephrotic syndrome regardless of level of proteinuria or specific treatment. The cause of the high plasma zonulin levels and whether zonulin contributes to glomerular injury requires further study

Urinary Epidermal Growth Factor as a Marker of Disease Progression in Children With Nephrotic Syndrome.

Introduction: Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome. Methods: The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time. Results: Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m Conclusion: uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome